|Classification and external resources|
The classic blue sclerae of a person with osteogenesis imperfecta
Osteogenesis imperfecta (OI and sometimes known as brittle bone disease, or "Lobstein syndrome") is a congenital bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen. This deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the collagen triple helix structure. The larger amino acid side-chains create steric hindrance that creates a bulge in the collagen complex, which in turn influences both the molecular nanomechanics as well as the interaction between molecules, which are both compromised. As a result, the body may respond by hydrolyzing the improper collagen structure. If the body does not destroy the improper collagen, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness. Another suggested disease mechanism is that the stress state within collagen fibrils is altered at the locations of mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate loads as the homogeneous stress state found in healthy collagen fibrils is lost. These recent works suggest that OI must be understood as a multi-scale phenomenon, which involves mechanisms at the genetic, nano-, micro- and macro-level of tissues.
As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen. Most cases have been caused by mutations in the COL1A1 and COL1A2 genes. In the past several years, there has been the identification of autosomal recessive forms. Most people with OI receive it from a parent but in 35% of cases it is an individual (de novo or "sporadic") mutation.
In dogs, OI is an autosomal-recessive condition. In Golden Retrievers it is caused by a mutation in the COL1A1, and in Beagles, the COL1A2. A separate mutation in the SERPINH1 gene has been found to cause the condition in Dachshunds.
There are eight different types of OI, Type I being the most common, though the symptoms vary from person to person.
|Type||Description||Gene||OMIM||Mode of Inheritance|
|I||mild||Null COL1A1 allele||166240 (IA), 166200 (IB)||autosomal dominant, 60% de novo |
|II||severe and usually lethal in the perinatal period||COL1A1, COL1A2,||166210 (IIA), 610854 (IIB)||autosomal dominant, ~100% de novo |
|III||considered progressive and deforming||COL1A1, COL1A2||259420||autosomal dominant, ~100% de novo |
|IV||deforming, but with normal scleras||COL1A1, COL1A2||166220||autosomal dominant, 60% de novo |
|V||shares the same clinical features of IV, but has unique histologic findings ("mesh-like")||IFITM5||610967||autosomal dominant |
|VI||shares the same clinical features of IV, but has unique histologic findings ("fish scale")||SERPINF1||610968||autosomal recessive |
|VII||associated with cartilage associated protein||CRTAP||610682||autosomal recessive |
|VIII||severe to lethal, associated with the protein leprecan||LEPRE1||610915||autosomal recessive|
Type I 
Collagen is of normal quality but is produced in insufficient quantities:
- Bones fracture easily
- Slight spinal curvature
- Loose joints
- Poor muscle tone
- Discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color. The blue-gray color of the sclera is due to the underlying choroidal veins which show through. This is due to the sclera being thinner than normal because of the defective Type I collagen not forming correctly.
- Early loss of hearing in some children
- Slight protrusion of the eyes
IA and IB are defined to be distinguished by the absence/presence of dentinogenesis imperfecta (characterized by opalescent teeth; absent in IA, present in IB). Life expectancy is slightly reduced compared to the general population due to the possibility of fatal bone fractures and complications related to OI Type I such as basilar invagination.
Type II 
Collagen is not of a sufficient quality or quantity
- Most cases die within the first year of life due to respiratory failure or intracerebral hemorrhage
- Severe respiratory problems due to underdeveloped lungs
- Severe bone deformity and small stature
Type II can be further subclassified into groups A, B, C, which are distinguished by radiographic evaluation of the long bones and ribs. Type IIA demonstrates broad and short long bones with broad and beaded ribs. Type IIB demonstrates broad and short long bones with thin ribs that have little or no beading. Type IIC demonstrates thin and longer long bones with thin and beaded ribs.
Type III 
Collagen improperly formed. Enough collagen is made but it is defective
- Bones fracture easily, sometimes even before birth
- Bone deformity, often severe
- Respiratory problems possible
- Short stature, spinal curvature and sometimes barrel-shaped rib cage
- Triangular face
- Loose joints
- Poor muscle tone in arms and legs
- Discolouration of the sclera (the 'whites' of the eyes)
- Early loss of hearing possible
Type III is distinguished among the other classifications as being the "Progressive Deforming" type, wherein a neonate presents with mild symptoms at birth and develops the aforementioned symptoms throughout life. Lifespan may be normal, albeit with severe physical handicapping.
Type IV 
Collagen quantity is sufficient but is not of a high enough quality
- Bones fracture easily, especially before puberty
- Short stature, spinal curvature and barrel-shaped rib cage
- Bone deformity is mild to moderate
- Early loss of hearing
Similar to Type I, Type IV can be further subclassified into types IVA and IVB characterized by absence (IVA) or presence (IVB) of dentinogenesis imperfecta.
Type V 
Same clinical features as Type IV. Distinguished histologically by "mesh-like" bone appearance. Further characterized by the "V Triad" consisting of a) radio-opaque band adjacent to growth plates, b) hypertrophic calluses at fracture sites, and c) calcification of the radio-ulnar interosseous membrane.
OI Type V leads to calcification of the membrane between the two forearm bones, making it difficult to turn the wrist. Another symptom is abnormally large amounts of repair tissue (hyperplasic callus) at the site of fractures. Other features of this condition include radial head dislocation, long bone bowing and mixed hearing loss.
Type VI 
Same clinical features as Type IV. Distinguished histologically by "fish-scale" bone appearance.
Type VII 
- In 2006 a recessive form called "Type VII" was discovered (Phenotype severe to lethal). Thus far it seems to be limited to a First Nations people in Quebec. Mutations in the gene CRTAP causes this type.
Although Type VII is indeed associated with First Nations people in Northern Quebec, the reference cited in this review is not supportive of that fact. It doesn't mention anything about First Nations, aboriginal, Native American, American Indian, or indigenous peoples.
Type VIII 
Other genes 
A family with recessive osteogenesis imperfecta has been reported to have a mutation in the TMEM38B gene on chromosome 9. This gene encodes TRIC-B a component of TRIC, a monovalent cation specific channel involved in calcium release from intracellular stores.
It is extremely likely that there are other genes associated with this disease that have yet to be reported.
At present there is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility.
There have been many clinical trials performed with Fosamax (Alendronate), a drug used to treat those experiencing brittleness of bones due to osteoporosis. Higher levels of effectiveness apparently are to be seen in the pill form versus the IV form, but results seem inconclusive. The U.S. Food and Drug Administration (FDA) will not approve Fosamax as a treatment for OI because long term effects of the drug have not been fully researched yet, although it is often used in preteens, instead of Pamidronate.
Although there is no known cure for OI, regular weight-bearing exercise, a diet rich in calcium and vitamin D, a healthy lifestyle, and, in some cases, vitamin supplements will help off-set early development of osteoporosis, prevent future fractures, and delay other health concerns related to OI.
Physiotherapy used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture. This often involves hydrotherapy and the use of support cushions to improve posture. Individuals are encouraged to change positions regularly throughout the day in order to balance the muscles which are being used and the bones which are under pressure.
Children often develop a fear of trying new ways of moving due to movement being associated with pain. This can make physiotherapy difficult to administer to young children.
Physical aids 
With adaptive equipment such as crutches, wheelchairs, splints, grabbing arms, and/or modifications to the home many individuals with OI can obtain a significant degree of autonomy.
Bisphosphonates (BPs), particularly those containing nitrogen, are being increasingly administered to increase bone mass and reduce the incidence of fracture. BPs can be dosed orally (e.g. alendronate) or by intravenous injection/infusion (e.g. pamidronate, zoledronic acid).
BP therapy is being used increasingly for the treatment of OI. It has proven efficiency in reducing fracture rates in children, however only a trend towards decreased fracture was seen in a small randomized study in adults. While decreasing fracture rates, there is some concern that prolonged BP treatment may delay the healing of OI fractures, although this has not been conclusively demonstrated.
Pamidronate is used in USA, UK and Canada. Some hospitals, such as most Shriners, provide it to children. Some children are under a study of pamidronate. Marketed under the brand name Aredia, Pamidronate is usually administered as an intravenous infusion, lasting about three hours. The therapy is repeated every three to six months, and lasts for the life of the patient. Common side effects include bone pain, low calcium levels, nausea, and dizziness. According to recent results, extended periods of pamidrinate, (i.e.;6 years) can actually weaken bones, so patients are recommended to get bone densities every 6 months-1 year, to monitor bone strength.
Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield, MD, at Shriners Hospitals for Children in Chicago. During the late 1940s, Sofield, Chief of Staff at Shriners Hospitals in Chicago, worked there with large numbers of children with OI and experimented with various methods to strengthen the bones in these children. In 1959, with Edward A. Miller, MD, Sofield wrote a seminal article describing a solution that seemed radical at the time: the placement of stainless steel rods into the intramedullary canals of the long bones to stabilize and strengthen them. His treatment proved extremely useful in the rehabilitation and prevention of fractures; it was adopted throughout the world and still forms the basis for orthopedic treatment of OI.
Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility makes this operation more complex in OI patients. Surgery for basilar impressions can be carried out if pressure being exerted on the spinal cord and brain stem is causing neurological problems.
The condition, or types of it, has had various other names over the years and in different nations. Among some of the most common alternatives are Ekman-Lobstein syndrome, Vrolik syndrome, and the colloquial glass-bone disease. The name osteogenesis imperfecta dates to at least 1895 and has been the usual medical term in the 20th century to present. The current four type system began with Sillence in 1979. An older system deemed less severe types "osteogenesis imperfecta tarda" while more severe forms were deemed "osteogenesis imperfecta congenita." As this did not differentiate well, and all forms are congenital, this has since fallen out of favour.
The condition has been found in an Ancient Egyptian mummy from 1000 BC. The Norse king Ivar the Boneless may have had this condition as well. The earliest studies of it began in 1788 with the Swede Olof Jakob Ekman. He described the condition in his doctoral thesis and mentioned cases of it going back to 1678. In 1831, Edmund Axmann described it in himself and two brothers. Jean Lobstein dealt with it in adults in 1833. Willem Vrolik did work on the condition in the 1850s. The idea that the adult and newborn forms were the same came in 1897 with Martin Benno Schmidt.
Frequency is approximately the same across groups, but for unknown reasons the Shona and Ndebele of Zimbabwe seem to have a higher proportion of Type III to Type I than other groups. However, a similar pattern was found in segments of the Nigerian and South African population. In these varied cases the total number of OIs of all four types was roughly the same as any other ethnicity.
Noted cases 
- American actors Michael J. Anderson, Tarah Lynne Schaeffer (Sesame Street) and Atticus Shaffer
- Leo Beuerman, subject of the documentary Leo Beuerman, which was nominated for the Academy Award for Best Documentary (Short Subject).
- British actors Julie Fernandez, Nabil Shaban, and Kerry Ingram.
- British peer Nicky Chapman, Baroness Chapman
- Randy Guss, drummer for Toad the Wet Sprocket
- Hip-hop artist and producer Kalyn Heffernan
- American Olympic bronze medalist coxswain Doug Herland
- Paralympic gold and bronze medalist in sledge hockey, Taylor Lipsett
- Zimbabwean marimba player Energy Maburutse
- Japanese countertenor singer Yoshikazu Mera
- Jazz pianist Michel Petrucciani
- Parsi playwright Firdaus Kanga
- Guinness World Records' shortest man He Pingping
- Motivational speaker Sean Stephenson
- French speaking poet and novelist Philippe Rahmy, Type I.
- Australian reality TV personality Quentin Kenihan 
- Lead singer of the Australian alternative rock group "The White Room" Marc Collis 
- Kid President aka Robby Novak (child comedian)
Historical figures whose OI status is disputed 
- French artist Henri de Toulouse-Lautrec. He was never diagnosed, and recent theories suggest that he had a mild form of osteopetrosis instead. Maroteaux and Lamy have suggested pyknodysostosis as the explanation.
- Viking invader of England, Ivar the Boneless. There is notable speculation about his physical condition, but since, 200 years after his death, his skeleton was exhumed and burnt by William I of England, objective diagnosis is not possible.
In media 
Figures in film, television, video games and novels depicted as having osteogenesis imperfecta include:
- (1998) British actor and writer Firdaus Kanga, who wrote and starred in the 1998 BBC film Sixth Happiness partially based on his own life. Kanga wrote Trying to Grow exploring the life of adolescents with this condition. Kanga featured on Channel 4 documentaries 'Taboo' and 'Double the Trouble, Twice the Fun,' exploring religion, sexuality and disability.
- (2000) The film Unbreakable features a character played by Samuel L. Jackson named Elijah Price who suffers from OI and is nicknamed "Mr. Glass" due to the brittleness of his bones.
- (2001) Raymond Dufayel (sometimes simply called "the glass man" by his neighbors) in the French film Amélie; Dufayel is depicted as being confined to his house (the interior of which is heavily padded) by the condition.
- (2005) The movie Fragile features a child with this condition.
- (2005) Dean Koontz's novel Forever Odd features a character named Danny Jessup who has OI and has been Odd Thomas's close friend since boyhood. Odd combs Pico Mundo and its environs searching for Danny after he has been abducted by his stepfather's killer.
- (2006) The fifth season of the series Scrubs saw Elliot Reid doing research into the various types of therapy available to O.I. patients. Her co-fellow Charlie then developed a new "gene therapy" cure, putting Elliot out of work.
- (2007) Jeff "Joker" Moreau, a frigate pilot in the popular video game series Mass Effect is depicted as suffering from Vrolik's Syndrome, requiring crutches or medical enhancements to perform simple tasks such as walking.
- (2009) Jodi Picoult wrote Handle with Care, a story about a little girl named Willow who has type III OI. The book shows how her disease has affected her life and the lives of those around her.
- (2013) Kid President, a YouTube sensation, suffers from the disorder but often comments on his own ability to overcome it.
See also 
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|Wikimedia Commons has media related to: Osteogenesis imperfecta|
- GeneReview/NCBI/NIH/UW entry on Osteogenesis Imperfecta
- synd/1743 at Who Named It?
- Overview at NIAMS
- Type V Research, Osteogenesis Imperfecta association